Alcohol intake has been implicated as a cause for refractory hypertension which constitutes a major health problem. The nature and the mechanism(s) of the hemodynamic interaction between alcohol and different antihypertensive medications, which may vary both in magnitude and direction, have received little attention. The general aim of the proposed studies is to focus on the mechanism(s) of the antagonistic hemodynamic interaction between alcohol and centrally acting antihypertensive drugs. Renewed interest in utilizing this class of drugs and particularly the second generation drugs, e.g. rilmenidine, as a first line monotherapy for the treatment of hypertension makes the proposed studies noteworthy. The newer drugs lack the sedative side effect of clonidine but lower blood pressure by the same mechanism. The proposed studies will therefore focus on the action of ethanol on the primary processes that lead to the hypotensive responses elicited by this class of drugs which are triggered by activation of the imidazoline receptor complex at their major site of action, the rostral ventrolateral medulla. Given the widespread use of alcohol, studies that deal with its action on the central pathways involved in the hemodynamic responses elicited by centrally acting drugs are warranted. The first aim is intended. to gain support to the hypothesis that the adverse effect of alcohol is targeted against the subclass of centrally acting drugs that lower blood pressure by activating the imidazoline receptor complex. The second aim is to investigate the mechanism(s) of this adverse hemodynamic interaction. The hypothesis is tested that the adverse hemodynamic effects of ethanol involve reversal of the electrochemical responses triggered by clonidine or rilmenidine at their major site of the hypotensive action, the rostral ventrolateral medulla (RVLM) via a selective interaction with the nonadrenergic imidazoline receptor complex. Further studies will determine the site and receptor selectivity of the action of ethanol. The third aim is to test the hypothesis that attenuation of the hypotensive responses elicited by clonidine administered concurrently with alcohol or acutely to alcohol-fed rats involves alcohol evoked modification of the binding characteristics of the imidazoline receptor complex in the rostral ventrolateral medulla, the major site of the hypotensive action of clonidine and the second generation drugs. Whether a pharmacokinetic interaction is involved in the chronic infraction between alcohol and clonidine will be investigated. The experiments proposed herein are intended to test these hypotheses in unrestrained conscious spontaneously hypertensive and normotensive rats chronically instrumented for hemodynamic and electrochemical measurements. These studies are expected to provide significant new insights about the effect of ethanol intake on the hypotensive responses elicited by activating central imidazoline receptors and the mechanism(s) of this health related hemodynamic interaction. In addition to gaining basic knowledge about the neurobiological effects of alcohol on the cardiovascular system, these studies are expected to yield clinically relevant information that could have significant outcome on the treatment of hypertension in alcohol using individuals.